Identification of novel treatment and biomarkers based on pharmacokinetics in patients with hepatocellular carcinoma

• Project/Area Number: 15K08077
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Nara Medical University
• Principal Investigator: Namisaki Tadashi 奈良県立医科大学, 医学部, 講師 (20526850)
• Co-Investigator(Kenkyū-buntansha): 野口 隆一 奈良県立医科大学, 医学部附属病院, 研究員 (30423908) ; 吉治 仁志 奈良県立医科大学, 医学部, 教授 (40336855) ; 北出 光輝 奈良県立医科大学, 医学部, 学内講師 (40526795)
• Co-Investigator(Renkei-kenkyūsha): Moriya Kei 奈良県立医科大学, 医学部, 講師 (40526852)
• Research Collaborator: Nishimura Norihisa 奈良県立医科大学, 医学部附属病院, 研究員
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 胆汁酸 / 肝線維化 / 肝癌 / OCT1 / FXR / farnesoid X receptor / ウルソデオキシコール酸

Outline of Final Research Achievements

We aimed to investigate the combined effect of FXR agonist and angiotensin II type 1 receptor blocker (ARB) on hepatic fibrogenesis in rat model of NASH.The in vitro and in vivo effects of an FXR agonist (INT747 at 30 mg/kg/day) and an ARB (Losartan: 30 mg/kg/day) on hepatic fibrogenesis were evaluated.In PS-administered OLETF rats, INT747 and losartan had potent inhibitory effects on hepatic fibrogenesis with suppression of HSC activation and expression of transforming growth factor (TGF)-β1 and TLR4. INT747 decreased intestinal permeability by ameliorating zonula occuludens-1 (ZO-1) disruption, whereas losartan directly suppressed the regulation of Ac-HSC. The in vitro and in vivo inhibitory effects of INT747 and losartan on TGF-β1 and TLR4 mRNA expression in Ac-HSC were almost in parallel. Losartan directly inhibited the regulation of Ac-HSC. Combined treatment may represent a promising novel approach for NASH.

Research Products

• [Journal Article] Effect of combined farnesoid X receptor agonist and angiotensin Ⅱtipe 1 receptor blocker on hepatic fibrosis. (2017)
  • Author(s): Namisaki T. Moriya K, Kitade M, Takeda K, Kaji K, Okura Y, Shimozato N. Sato S, Nishimura N, Seki K, Kawaratani H, Takaya H, Sawada Y, Akahane T, Saikawa S, Nakanishi K, Kubo T, Furukawa M, Noguchi R, Asada K, Kitagawa K, Ozutsumi T, Tsuji Y, Kaya H Yoshiji
  • Journal Title: Hepatol commun. Volume: 1 Issue: 9 Pages: 928945-928945
  • DOI: 10.1002/hep4.1104
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide Association Study Identifies TLL1 Variant Associated With Development of Hepatocellular Carcinoma After Eradication of Hepatitis C Virus Infection. (2017)
  • Author(s): Matsuura K, Honda M, et al.
  • Journal Title: Gastroenterology. Volume: - Issue: 6 Pages: 1383-1394
  • DOI: 10.1053/j.gastro.2017.01.041
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical significance of the Scheuer histological staging system for primary biliary cholangitis in Japanese patients. (2017)
  • Author(s): Namisaki T, Moriya K, Kitade M, Kawaratani H, Takeda K, Okura Y, Takaya H, Nishimura N, Seki K, Kaji K, Sato S, Sawada Y, Yamao J, Mitoro A, Uejima M, Mashitani T, Shimozato N, Nakanishi K, Furukawa M, Saikawa S, Kubo T, Yoshiji H.
  • Journal Title: Eur J Gastroenterol Hepatol. Volume: 29 Pages: 23-30
  • Peer Reviewed
• [Journal Article] Combined treatment with dipeptidyl peptidase-4 inhibitor (sitagliptin) and angiotensin-II type 1 receptor blocker (losartan) suppresses progression in a non-diabetic rat model of steatohepatitis. (2016)
  • Author(s): Okura Y,Yoshiji H.
  • Journal Title: Hepatol Res Volume: Dec28 Issue: 12 Pages: 1317-1328
  • DOI: 10.1111/hepr.12860
  • Peer Reviewed
• [Journal Article] Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis. (2016)
  • Author(s): Namisaki T, Noguchi R, Moriya K, Kitade M, Aihara Y, Douhara A, Nishimura N, Takeda K, Okura Y, Kawaratani H, Takaya H, Seki K, Yoshiji H
  • Journal Title: Ｊｏｕｎａｌ ｏｆ Ｇａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ Volume: ５１ Issue: 2 Pages: 162-72
  • DOI: 10.1007/s00535-015-1104-x
  • Peer Reviewed
• [Presentation] Effect of nalfurafine hydrochloride for refractory pruritus in patients with primary biliary cholangitis: a multicenter, postmarketing single-arm, prospective study (2018)
  • Author(s): Yagi M, Tanaka A, Namisaki T, Abe M, Takahashi A, Honda A, Matsuzaki Y, Ohira H, Yoshiji H, Takikawa H
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Biochemical response to ursodeoxycholic acid predicts histologic primary ciliary cholangitis progression (2018)
  • Author(s): Namisaki T, Fujinaga Y, Moriya K, Kitade M, Kaji K, Kawaratani H, Seki K, Takaya H, Sato S, Sawada Y, Akahane T, Yoshji H
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Are the Globe and UK-PBC scrore also effective for predicting risk in patients treated with bezafibrate in addition to ursodeoxycholic acid?:A validation study in Japan (2018)
  • Author(s): Tanaka A, Komori A, Abe M, Inao M, Namisaki T, Hashimoto N, Kawata K, Takahashi A, Ninomiya M, Honda A, Hong-Hon K, Arakawa M, Yamagiwa S, Joshita S, Sato K, Kaneko A, Kikuchi K, Itakura J, Nomura T, Kakisaka K, Yoshji H, and et al.
  • Organizer: EASL
  • Int'l Joint Research
• [Presentation] Biochemical response to ursodeoxycholic acid predicts histologic primary biliary cholangitis progression (2018)
  • Author(s): Fujinaga Y, Namisaki T, Moriya K, Kitade M, Kawaratani H, Kaji K, Okura Y, Seki K, Takaya H, Sawada Y, Akahane T, Nishimura N, Sato S, Shimozato N, Saikawa S, Nakanishi K, Kubo T, Furukawa M, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Beneficial effects of combined farnesoid X receptor agonist(INT747) and dipeptidyl peptidase-4 inhibitor(sitagliptin) on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis (2017)
  • Author(s): Shimozato N, Namisaki T, Moriya K, Kitade M, Takeda K, Kawaratani H, Kaji K, Okura Y, Takaya H, Sawada Y, Nishimura N, Sato S, Saikawa S, Seki K, Furukawa M, Nakanishi K, Kubo T, Yoshiji H
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Bezafibrate improves GLOBE and UK-PBC scores and long-term outcomes in patients with primary biliary cholangitis (2017)
  • Author(s): Honda A, Tanak A, Komori A, Abe M, Inao M, Moshida S, Namisaki T, Yoshiji H, Hashimoto N, Kawata K, Takahashi A, Ohira H, and et al.
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Pruritus, dryness, fatigue and health-related quality of life in Japanese patients with primaty biliaty cholangitis (2017)
  • Author(s): Yagi M, Tanaka A, Abe M, Namisaki T, Yoshiji H, Takahashi A, Ohira H, Komori A, Yamagiwa S, and et al.
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] Combination treatment of dipeptidyl peptidase IV inhibitor and angiotensin-II type 1 receptor blocker attenuates progression of nonalcoholic steatohepatitis in rats (2016)
  • Author(s): Shinya Sato, Tadashi Namisaki, Kosuke Kaji, Norihisa Nishimura, Yasushi Okura, Ryuichi Noguchi, Kosuke Takeda, Kei Moriya, Mitsuteru Kitade, Kenichiro Seki, Hiroaki Takaya, Hideto Kawaratani, Yasuhiko Sawada, Naotaka Shimozato, Keisuke Nakanishi, Hitoshi Yoshiji
  • Organizer: アメリカ肝臓学会
  • Place of Presentation: ボストン US
  • Year and Date: 2016-11-11
• [Presentation] Antifibrotic effects of combined treatment with Farnesoid X receptor agonist and angiotensin-II type1 receptor blocker on hepatic fibrogenesis in the rat model of nonalcoholic steatohepatitis (2016)
  • Author(s): Tadashi Namisaki, Yasushi Okura, Shinya Sato, Ryuichi Noguchi, Kei Moriya, Mitsuteru Kitade, Kosuke Takeda, Yosuke Aihara, Norihisa Nishimura, Yasuhiko Sawada, Kenichiro Seki, Hideto Kawaratani, Kosuke Kaji, Hitoshi Yoshiji.
  • Organizer: ヨーロッパ肝臓学会
  • Place of Presentation: バルセロナ スペイン
  • Year and Date: 2016-04-13
• [Patent(Industrial Property Rights)] FXRアゴニストとARBの組み合わせ医薬 (2017)
  • Inventor(s): 浪崎正
  • Industrial Property Rights Holder: 浪崎正
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] FXRアゴニストとARBの組み合わせ医薬 (2017)
  • Inventor(s): 浪崎正
  • Industrial Property Rights Holder: 浪崎正
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017
  • Overseas
• [Patent(Industrial Property Rights)] [PCT出願] PCT/JP2017/012448 (2017)
  • Inventor(s): 浪崎 正、吉治 仁志
  • Industrial Property Rights Holder: 大日本住友製薬株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-03-27
  • Overseas
• [Patent(Industrial Property Rights)] [台 湾出願] 106110180 (2017)
  • Inventor(s): 浪崎 正、吉治 仁志
  • Industrial Property Rights Holder: 大日本住友製薬株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-03-27
  • Overseas
• [Funded Workshop] 第25回アジア太平洋肝臓病学会議年次総会（APASL2016 ... (2016)
  • Place of Presentation: 東京
  • Year and Date: 2016-02-20